tbuckley/cabot-search huggingface dataset:
Novel GUCY2C targeting CAR-T therapy: Efficacy in advanced colorectal cancer.
Authors: Qianyu Zhang, Lin Lin, Lin Wang, Wei Wang, Liting Qian, Yueyin Pan, Hu Liu
Journal: Journal of Clinical Oncology (2023)

3559 Background: Chimeric antigen receptor (CAR) T cells have shown remarkable success in treating patients with hematologic malignancies. However, the majority of CAR-T cell clinical trials in solid tumors have limited success which is partially attributed to the detrimental tumor microenvironment and the lack of ideal target. Recently, GUCY2C emerges as an ideal therapeutic target which is highly expressed in colorectal cancer (CRC). Here, a novel nanobody-based GUCY2C targeting CAR-T cell developed by us is applied to treat advanced colorectal cancer patients who failed third-line therapy. Methods: In this open-label, single-arm, investigator-initiated exploratory trial (ChiCTR2100044831), we primarily explore the safety and the low-dose efficacy of the autologous anti-GUCY2C CAR-T cells. All patients screened by IHC met our criteria for GUCY2C positivity. All enrolled patients had received at least 3 prior lines of therapy and had multiple metastases at baseline. Totally, 13 advanced CRC patients aged 18 to 65 years were infused with the anti-GUCY2C CAR-T cells at a dose range of 0.5-3 x10e6/kg after standard Cy-Flu lymphodepletion. Adverse events (AE) were graded according to CTCAE 5.0, and objective tumor responses were assessed per RECIST 1.1 criteria. Results: Between November 2021 and December 2022, 13 subjects with refractory metastatic CRC (mCRC) were treated with the anti-GUCY2C-CAR-T cells infusions at a dose range of 0.5-3 x10e6/kg. There were no dose-limiting toxicities, treatment-related death or any form of neurotoxicity occurred in this study. The most common TEAEs were diarrhea in 9/13 (69%) subjects (Grade 1: 2/13 (15.38%) Grade 2: 3/13 (23.07%) Grade 3: 4/13 (30.77%)). 8/13 (62%) mCRC subjects experienced grade1 or grade 2 mouth ulcer generally appear as a single lesion lasting for a few days. All cytokine release syndromes (CRS) observed were grade 1. Totally 9 pts (69%) experienced grade 1 CRS and all resolved by supportive care without the need of tocilizumab. No grade 4 AEs except for decreased lymphocytes in 12/13 pts (92%), decreased white blood cells in 1/13 pts (7.7%) and decreased platelet in 1/13 pts (7.7%). Among 10 evaluable patients, 6 partial responses, 2 stable disease and 2 progressive disease were achieved. At all dose levels ORR and DCR were 60% and 80% respectively. Notably, all 3 patients infused at the dose level above 2x10e6/kg reached partial responses. Among the 3 non-evaluable patients, 1 patient lost follow-up, 1 patient died of bone marrow failure and 1 patient died of COVID-19 related complications before the first efficacy evaluation. Additional data will be presented at the meeting. Conclusions: This clinical study indicated that the anti-GUCY2C CAR-T cell therapy was well tolerated and had promising efficacy in heavily pretreated mCRC patients. Clinical trial information: ChiCTR2100044831 .
Understanding differences in the rates of BRCA/HRD testing and treatment in 1<sup>st</sup> line maintenance in patients with ovarian cancer treated by gynecologic oncologists compared to other providers: A quality initiative by Integra Connect (IC) PrecisionQ.
Authors: Fred J. Kudrik, Mike Gart, Simon Blanc, Sandy English, Erin Alwon
Journal: Journal of Clinical Oncology (2023)

5576 Background: The role of PARPi in the treatment of advanced ovarian cancer (aOC) has expanded in recent years. In this context, South Carolina Oncology Associates (SCOA) partnered with Integra Connect (IC) on a quality initiative (QI) to evaluate the rate of BRCA and HRD testing in newly diagnosed OC patients and the use of maintenance therapy in the 1st line (1L) setting in aOC. Patients with aOC at SCOA are typically managed by gynecologic oncologists. Methods: Using the IC Precision Q real-world database of over 1 million cancer patients across 275 sites of care, we assessed newly diagnosed OC patients evaluated via medical chart curation from 1/1/2020 to 6/30/2022 for BRCA and HRD testing at SCOA (N = 81) and other oncology practices (N = 1,045). We also studied the use of maintenance therapy in patients with stage II-IV OC who completed platinum-based chemotherapy from 1/1/2020 to 6/30/2022 at SCOA (N = 75) and other oncology practices (N =899). SCOA was compared to other oncology practices in terms of provider specialty treating the patient, rates of HRD and BRCA testing, and use of 1L maintenance treatment in patients with or without BRCA or HRD mutations. Descriptive analyses were used. Proportions were compared using a two tailed two sample z-test. Results: Among newly diagnosed patients at SCOA, 95% of patients with OC were primarily managed by a gynecologic oncologist compared to 5% at other practices. The rate of BRCA testing at SCOA was 81% (66 of 81) compared to 75% (788 of 1045) and HRD testing was 60% (49 of 81) compared to 39% (403 of 1045) at other oncology practices in the IC database. The difference in HRD testing was significant (p &lt; 0.01). The use of 1L maintenance regardless of biomarker status was 64% (48 of 75) at SCOA compared to 50% (449 of 899) at other practices. The difference in 1L maintenance use was significant (p&lt;0.05). PARPi were used at SCOA for maintenance therapy in 82% (38 of 46) of patients compared to 74% (314 of 427) at other practices. The use of maintenance in BRCA or HRD positive patients was 84% (21 of 25) at SCOA compared to 75% (151 of 201) for other practices. Conclusions: In this real-world study, treatment by gynecologic oncologists was associated with higher rates of BRCA and HRD testing and higher use of 1L maintenance treatment in patients with aOC compared to other practices. These findings underscore the importance of gynecologic oncologists in the management of aOC to ensure optimal testing and adherence to treatment guidelines.
Using machine learning-based boosting algorithm to predict hepatotoxicity after local therapy and association with survival in patients undergoing liver directed therapy.
Authors: Allen Mo, Christian Velten, Justin Tang, Nitin Ohri, Shalom Kalnicki, Parsa Mirhaji, Andreas Kaubisch, Selvin Soby, Alexandre Peshansky, Erin Henninger, Madhur Garg, Chandan Guha, Rafi Kabarriti
Journal: Journal of Clinical Oncology (2023)

e16229 Background: Hepatocellular carcinoma typically arises in the setting of chronic liver disease. In carefully selected patients, liver directed therapy has been demonstrated to improve survival; however, this benefit from cancer specific survival may be offset by increased mortality from diminished hepatic functional reserve. Treatment-related hepatotoxicity also may vary between liver directed treatment modalities for a given tumor. Our aim was to determine if a machine learning approach could estimate hepatotoxicity prior to treatment. Methods: We identified all patients with hepatocellular carcinoma who underwent liver directed therapy at a large urban academic health system who also had post-treatment laboratory follow-up at 6 months. Patients were categorized as having worse liver function if they experienced a decline in albumin-bilirubin (ALBI) grade or more than 0.5 absolute decline in ALBI score at post treatment follow-up. A machine learning, extreme-gradient boosting (XGBoost) approach was employed to identify predictive features for hepatotoxicity using fine-tuned hyperparameters. Results: The study cohort consisted of 269 patients. 48 (18%) were categorized as having worsened hepatic function after liver directed therapy, with an average decline of -0.72 in ALBI score. Median survival after liver directed therapy was 5.8 years, with worsening hepatic function associated with a 5 month decline in overall survival. 158 (59%) patients received transarterial chemoembolization, 99 (37%) patients received stereotactic body radiotherapy and 12 (7%) patients received Y-90. A machine learning model was developed resulting in an Area Under the ROC Curve (AUC) of 0.894 in a 10-point decision tree model. On SHAP analysis, the features with the largest impact on hepatotoxicity prior to treatment was pretreatment T-stage followed by Child-Pugh Score. Conclusions: A machine learning model was developed to accurately classify patients who sustained treatment related hepatotoxicity. Significant decline in ALBI score or grade was associated with a worsening of overall survival. Future studies in larger prospective clinical trials utilizing this machine learning-based methodology of assessing liver dysfunction after focal therapy are required to validate these findings.
BRUIN CLL-314: A phase 3, open-label, randomized study of pirtobrutinib versus ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.
Authors: Jennifer Ann Woyach, Catherine Callaghan Coombs, Katharine L. Lewis, Maricer P. Escalon, Matteo Ceccarelli, Yuanyuan Faith Bian, William G. Wierda
Journal: Journal of Clinical Oncology (2023)

TPS7584 Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these agents are not curative. cBTKi share pharmacologic liabilities such as low oral bioavailability and a short half-life that may lead to suboptimal BTK target coverage, especially in rapidly proliferating tumors with high BTK protein turnover, such as accelerating CLL/SLL, which can manifest as acquired resistance to cBTKi. Novel therapeutic agents addressing both intolerance and resistance while also improving efficacy are needed. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates (ORR) and was well tolerated in patients with CLL/SLL irrespective of prior therapy (including cBTKi), number of prior lines of therapy, BTK C481 mutation status, or reason for prior cBTKi discontinuation. The objective of this study is to compare efficacy and tolerability of pirtobrutinib versus ibrutinib in patients with CLL/SLL. Methods: BRUIN CLL-314 (NCT05254743) is a global, phase 3, open-label, randomized study comparing pirtobrutinib with ibrutinib. Approximately 650 BTKi-naïve patients, either treatment-naïve (up to 30%) or previously treated with other non-BTKi agents, will be randomized 1:1 to receive daily 200 mg pirtobrutinib once daily or 420 mg ibrutinib as continuous monotherapy. Randomization will be stratified by del(17p) status (yes/no) and number of prior lines of therapy (0 vs 1 vs ≥2). Enrollment for this study is ongoing. Adults with CLL/SLL who require therapy per iwCLL 2018 criteria are eligible. Key exclusion criteria include prior exposure to any BTKi, use of some concomitant therapies including anticoagulants, such as warfarin and other vitamin K antagonists, significant cardiovascular disease, active infections, and other clinically significant conditions. The primary objective is to establish non-inferiority of pirtobrutinib versus ibrutinib by comparing the ORR per iwCLL guidelines assessed by an independent review committee. Superiority of pirtobrutinib versus ibrutinib in progression-free survival is a key secondary outcome. Other endpoints include duration of response, overall survival, time-to-next treatment, tolerability, and patient-reported outcomes. Trial efficacy and safety will be monitored by an independent data monitoring committee. Clinical trial information: NCT05254743 .
Five-year overall survival with S-1 plus docetaxel as adjuvant treatment in curatively resected pStage III gastric cancer in JACCRO GC-07.
Authors: Wataru Ichikawa, Kazuhiro Yoshida, Yasuhiro Kodera, Masato Kitazawa, Motohiro Hirao, Yasuyuki Seto, Kenji Hibi, Shinichi Kinami, Masaya Watanabe, Shigeto Makino, Mitsugu Kochi, Takeshi Sano, Yoshihiro Kakeji, Masahiro Takeuchi, Masashi Fujii
Journal: Journal of Clinical Oncology (2023)

4065 Background: JACCRO GC-07 is a randomized controlled trial to explore postoperative S-1/docetaxel compared to S-1 alone after D2 gastrectomy for pStage III gastric cancer (GC) patients. The second interim analysis demonstrated that the significant improvement of RFS was obtained by S-1/docetaxel compared to S-1 alone. The study was terminated by the recommendation of independent data and safety monitoring committee (Yoshida K et al. J Clin Oncol 2019; 37:1296-1304). Preplanned analysis to evaluate RFS at 3 years, the primary endpoint, was also published (Kakeji Y et al. Gastric Cancer 2022; 25:186-196). We report the 5-years follow-up data from the trial. Methods: Patients with pStage III GC were randomly assigned to receive either S-1/docetaxel (S-1 80-120mg/body on days 1-14 with a 7-day rest followed by docetaxel 40mg/m 2 on day 1 and S-1 80-120mg/body on days 1-14 every 21 days for 6 cycles followed by S-1 80-120mg/body on days 1-28 every 42 days for 4 cycles) or S-1 (80-120mg/body on days 1-28 every 42 days for 8 cycles) after D2 gastrectomy. Blocked randomisation was performed and stratified by the stage (IIIA, IIIB, IIIC) and histological type (differentiated or undifferentiated). The primary endpoint was 3y RFS and the secondary endpoints were OS, TTF and safety. This analysis presents the final preplanned assessment of outcomes after 5 years. Results: Of 915 randomly assigned patients, 912 patients were included in the intention-to-treat (ITT) analysis. In the final analysis, 426 recurrences and 373 deaths were confirmed among the ITT population during the median follow-up period of 63.72 months (3.52-111.87). The 5y RFS of 59.8% in the S-1/docetaxel group was significantly superior to 50.6% in the S-1 group (HR 0.726, 95% CI: 0.599-0.879, p = 0.0010) and the 5y OS was 67.9% in the S-1/docetaxel group and that of S-1 group was 60.3%, respectively (HR 0.752, 95% CI: 0.613-0.922, p = 0.0059), confirming the significant improving effect on the survival of the patient. Conclusions: Adjuvant treatment with S-1 plus docetaxel should be considered for patients with pStage III gastric cancer who underwent D2 gastrectomy without neoadjuvant chemotherapy. Clinical trial information: UMIN000010337 .
A novel anti-HER2 monoclonal antibody IAH0968 in HER2-positive, heavily pretreated solid tumors: Results from a phase Ⅰa/Ⅰb, first-in-human, open-label, single-center study.
Authors: Na Song, Yuee Teng, Zan Teng, Jing Shi, Bo Jin, Jinglei Qu, Lingyun Zhang, Ping Yu, Lei Zhao, Jin Wang, Aodi Li, Linlin Tong, Yunpeng Liu, Xiujuan Qu
Journal: Journal of Clinical Oncology (2023)

e15098 Background: IAH0968 is an afucosylated anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody which possessing the same binding properties to HER2 as trastuzumab and improving antibody-dependent cellular cytotoxicity (ADCC) activity and superior anti-tumor efficacy. We present results from patients with advanced HER2 positive malignant solid tumors including trastuzumab resistant and ineffective patients to establish the recommended dose of IAH0968 for phase II trials, as well as to investigate the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of the drug. Methods: This was a single institution investigator-initiated phaseⅠa/Ⅰb study, using 3+3 design. The primary endpoint was safety, tolerability and preliminary clinical activity. Secondary endpoints included PK, recommended phase II dose, and anti-drug antibody (ADA). PK detection used ELISA to quantitatively determine blood drug concentration of IAH0968. Results: Eighteen pts were evaluable for safety and fifteen pts were suitable for efficacy analysis. The primary cancer sites included breast (8/18), colon (3/18), stomach (2/18), rectum (2/18), biliary tract (2/18), and pancreas (1/18). Median age was 54.2±9.7, ECOG 1/2 = 17/1, and 72.2% received anti-HER2 therapy in prior lines. Doses escalation were 6mg/kg (N = 3), 10mg/kg (N = 6), 15mg/kg (N = 5), and tolerable up to 20mg/kg (N = 4). Only one DLT was found at dosage 10mg/kg, and no MTD was reached. No ADA against IAH0968 was detected. The main PK parameters included mean T 1/2 for doses 6~20 mg/kg ranging from 105 to 118 hours. The volume of distribution (Vz -obs ) ranged from 4110.16 mL to 5395.64 mL. EC 50 of ADCC activity of IAH0968 was 17.75~63.25 ×10 -3 µg/mL. All grade treatment-related adverse events (TRAEs) occurred in 100% of pts, including grade 3 in 16.7%, and grade 4 in 5.6% of pts. The most common grade 3 TRAEs were hypokalemia (5.6%), arrhythmia (5.6%), QTC interval extension (5.6%), and infusion reaction (5.6%). The grade 4 TRAE was arrhythmia (5.6%). No serious TRAE or G5 were reported. 22.2% of pts had a TRAE leading to dose adjustment and 16.7% leading to discontinuation of IAH0968. After a median follow-up of 56.5 days (range, 0-479), objective response rate (ORR) was 13.3% (2/15), disease control rate (DCR) was 53.3% (8/15), and median progression-free survival (PFS) was 57.5 days (range, 42-236), with 4/15 responses ongoing. Conclusions: In heavily pretreated metastatic pts with HER2 positive, IAH0968 demonstrated promising clinical activity and tolerable safety profiles. IAH0968 will be further assessed in Phase Ⅱ study in combination treatment. Clinical trial information: NCT04934514 .
Patient-reported outcomes during pelvic radiation therapy: A secondary analysis on sexual function from NRG-RTOG 1203.
Authors: Kelsey L Corrigan, Rebecca Paulus, Ann Klopp, Lari B. Wenzel, Anamaria R Yeung, J Spencer Thompson, Desiree E. Doncals, Vijayananda Kundapur, Nancy H Wiggers, Dasarahally S. Mohan, Sharad A. Ghamande, Shannon Neville Westin, Kara Schnarr, Michael Haas, David K. Gaffney, Steven E. Waggoner, Pamela Vanderwall, Noha Jastaniyah, Stephanie L. Pugh, Lisa A. Kachnic
Journal: Journal of Clinical Oncology (2023)

5533 Background: NRG-RTOG 1203 reported that intensity-modulated radiation therapy (IMRT) reduced patient-reported GI and GU toxicities in cervical/endometrial cancer patients receiving adjuvant RT, as compared to standard whole field pelvic RT (WPRT). We conducted a secondary analysis of patient-reported sexual function (PR-SF) to compare this endpoint among treatment groups and identify factors associated with sexual dysfunction. Methods: Patients on NRG-RTOG 1203 were randomly assigned to WPRT vs. IMRT and completed the PRO-CTCAE for GI toxicity and the cervical cancer FACT-Cx at baseline, week 5 of RT, and at 4-6 weeks, 1-year, and 3-years post-RT. Patient responses to FACT-Cx sexual function questions were analyzed. The between arm frequency and severity of responses were tested using chi-square. PR-SF was compared with PRO-CTCAE GI toxicity using chi-square. A repeated measures logistic regression model was used to determine the impact of clinical/treatment factors on sexual function by dichotomizing the responses. Results: Of the 279 patients included for primary analysis, 236 (85%) completed PR-SF questions; 125 (53%) in the WPRT arm and 111 (47%) IMRT. There were no significant differences in PR-SF between treatment groups (p&gt;0.05). PR-SF improved for both groups post-RT, except responses to “my vagina feels too narrow or short” worsened (Table). Women without abdominal pain interference at 4-6 weeks post-RT were less likely to fear sex (74.2% vs. 25.8%, P=0.03) and more likely to like their body appearance at 1 year (95.7% vs. 4.3%, P&lt;0.01) compared to women with interference. Women liked the appearance of their body less during RT vs. at baseline (OR 1.95, 95% CI 1.04-3.64, P=0.04). Women were less interested in sex during RT in both arms (WPRT: OR 3.61, 95% CI 1.40-9.34; IMRT: OR 3.96, 95% CI 1.02-15.34) and at 4-6 weeks post-RT for IMRT (OR 3.16, 95% CI 1.14-8.72) vs. at baseline. Conclusions: PR-SF was similar between treatment groups. PR-SF during and post-RT was not significantly reduced compared to baseline with the exception of patients with abdominal pain interference, who had significantly worse PR-SF at 4-6 weeks and 1-year post-RT. Clinical trial information: NCT01672892 . [Table: see text]
Predictors of long-term progression-free survival (PFS) in niraparib-treated patients (pts) from the PRIMA/ENGOT-OV26/GOG-3012 study.
Authors: Whitney Graybill, Beatriz Pardo, David M. O'Malley, Ignace Vergote, Bradley J. Monk, Annika Auranen, Larry J. Copeland, Roberto Sabbitini, Thomas J Herzog, Philippe Follana, Bhavana Pothuri, Elena Ioana Braicu, Colleen McCormick, Alfonso Yubero-Esteban, Richard G. Moore, Peter Vuylsteke, Nicoline Raashouu-Jensen, Whitney York, John Hartman, Antonio Gonzalez Martin
Journal: Journal of Clinical Oncology (2023)

5589 Background: Niraparib was approved as maintenance therapy for pts with advanced ovarian cancer (OC) after complete or partial response (CR/PR) to first-line (1L) platinum-based chemotherapy (CT) based on results from the PRIMA study. In this post hoc analysis, we identified factors associated with long-term PFS. Methods: PRIMA is a phase 3, randomized study of pts with newly diagnosed advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer at high risk for relapse with CR/PR after 1L platinum-based CT. Pts were randomized 2:1 to niraparib 200 or 300 mg or placebo QD, and stratified by best response to 1L CT (CR/PR), neoadjuvant CT (yes/no), and homologous recombination deficiency (HRD) status (deficient [HRd]/proficient or not determined [HRp/nd]). Investigator-assessed PFS was dichotomized in niraparib-treated pts with progressive disease (PD)/censoring &lt;2 years vs PD/censoring ≥2 years after randomization (data cut, Nov 17, 2021). Logistic regression modeling using backward elimination (significance level=0.15) was used to identify baseline covariates associated with long-term PFS. Results: Of 487 niraparib-treated pts, 152 (31%) had PD/censoring ≥2 years after randomization. Odds ratios (OR) for PFS ≥2 years by baseline subgroup are shown (Table). The logistic regression model showed that BRCA mutation and HRD status, International Federation of Gynecology and Obstetrics (FIGO) stage, fallopian tube as the site of the primary tumor, and absence of baseline nontarget lesions were associated with longer PFS. Eastern Cooperative Oncology Group (ECOG) performance score, body mass index, age, time from CT to randomization, number of target lesions, best response after CT, number of CT cycles, type of debulking surgery, and residual disease were not associated with PFS ≥2 years. Safety has been reported previously ( Ann Oncol. 2022;33[suppl 7]:S789). Conclusions: Results suggest that long-term PFS in pts treated with niraparib may be associated with BRCA/HRd biomarker status, FIGO stage, primary tumor site, and number of baseline non-target lesions. These data are hypothesis generating. Clinical trial information: NCT02655016 . [Table: see text]